A Diagnostic Approach to Adrenal Cortical Lesions
Anne Marie McNicol
Published online: 17 December 2008 C Humana Press Inc. 2008
Abstract The adrenal gland is not a common specimen in surgical pathology practice as, until recently, adrenal tumors were recognized in life only if associated with hypersecretion of hormones or evidence of malignancy. However, adrenal nodules are not uncommon at autopsy, and the number of these found in life is now increasing as they are identified when the abdomen is scanned for the investigation of other diseases using computed tomography or magnetic resonance imaging. It is therefore becoming increasingly important for the surgical pathologist to be aware of the range of pathology in the gland and to understand how to approach the specimens. This short review will deal with lesions of the adrenal cortex.
Keywords adrenal cortex · adenoma · carcinoma . immunohistochemistry · molecular genetics
Introduction
Adrenal gland resections are not common in surgical pathology and there are few guidelines as to how to deal with these specimens [1, 2]. Adrenal cortical disease is associated with a variety of clinical syndromes due to overproduction of glucocorticoids, aldosterone or sex
A. M. McNicol
Molecular and Cellular Pathology, School of Medicine, The University of Queensland, Brisbane, Australia
A. M. McNicol ( ☒ UQCCR, The University of Queensland,
Level 6, Building 71/918, Royal Brisbane and Women’s Hospital, Herston QLD 4029, Australia e-mail: a.mcnicol@uq.edu.au
steroids. Malignant adrenal tumors may present with local symptoms or distant metastases. However, the number of lesions found incidentally is increasing, as the advent of modern computed tomography (CT) and magnetic resonance imaging scanning techniques has led to asymptomatic adrenal lesions being identified when the abdomen is scanned for the investigation of other disease. It is important for the pathologist to know how to approach these specimens and to have an understanding of the range of pathology that can be found in the gland. The pathology found in the adrenal cortex will be discussed here. Only aspects of the medulla pertinent to the interpretation of cortical pathology will be included.
Normal Adrenal Cortex
Structure and Function
The normal adult adrenal gland weighs 4 g at surgical excision or in cases of sudden death. At hospital autopsy, the average is 6 g. This reflects the hypertrophy induced as a result of stimulation by adrenocorticotrophic hormone (ACTH) in the stress of terminal illness. The gland is divided into head, body, and tail with alae extending laterally. The medulla comprises about 10% of the total weight and is present in the head and body and focally in the alae. The cortex comprises three zones with characteristic histologic features. The zona glomerulosa (ZG) is composed of small angular cells with a high nuclear to cytoplasmic ratio dispersed focally under the capsule. It synthesizes the main mineralocorticoid, aldosterone. The major part is the zona fasciculata (ZF) with large clear lipid-laden cells arranged in columns from the capsule or ZG to the inner zona reticularis (ZR). It is now thought to be the major
source of glucocorticoids (cortisol in the human gland). The ZR comprises eosinophilic (compact) cells with little lipid storage arranged in cords around vascular sinusoids. This zone can also produce cortisol and appears to be the source of androgens.
General Approach to Adrenal Specimens
Clinical Information
In addition to general demographic information, the request form sent with the specimen should specify the clinical and radiologic findings. It is also helpful if relevant biochemical results are included.
Macroscopic Examination
The nature of the specimen and the side should be noted. The type of surgery is important, as laparoscopic removal may cause fragmentation of the gland and cause difficulty in the assessment of completeness of excision or invasion in tumors. It is often useful to have a photograph of the intact specimen and of the slices. The excision margins should be inked in tumor resections. The specimen should be weighed and measured in three dimensions. Although it would be usual practice to then dissect the specimen free of fat to obtain an accurate adrenal weight and measurements, this should not jeopardize the proper assessment of local invasion in the case of tumors.
Non-Tumoral Glands
The gland should be measured in three dimensions then sliced transversely where possible from head to tail at 2- to 3-mm intervals. The features of the cut surface should be noted, including the width of the cortex and any visible nodularity. The distribution of the medulla should be recorded. Representative blocks should be taken from head, body, and tail. Any focal lesions should also be sampled.
Adrenal Tumors
The tumor should be measured in three dimensions. The capsule should be examined for evidence of invasion or intraoperative damage. Although it is important to get an accurate weight, as indicated above, the fat should not be removed if there is suspicion of local invasion. The appearance of the cut surface should be noted, including the presence of necrosis and fibrosis. Where the adjacent adrenal is seen, it should be described and the relation to the tumor should be noted. There are no defined protocols for tumor sampling, but it has been suggested that lesions
less than 3 cm in diameter should be processed in their entirety [1]. Larger lesions should have an additional block for each 1 cm. The blocks should be selected as representative of the range of naked-eye appearances. Any areas where there is suspicion of invasion into surrounding tissues should be processed. Surgical margins should be sampled where required to assess completeness of excision. Representative blocks should be taken from the adjacent gland. The number of lymph nodes submitted or identified in the main specimen should be recorded. Any other tissues in the specimen should be examined.
Microscopic Examination
For non-tumoral specimens and para-tumoral glands, the width of the cortex and the pattern of zonation should be noted. The presence of nodules should be described, together with whether they are micronodules or macro- nodules. If possible, the appearance of the cortex between the nodules should be documented.
The histologic features of adrenal cortical tumors are discussed below.
Adrenal Cortical Tumors-General Features
Adrenal Cortical Nodules
Adrenal cortical nodules are reported in up to 54% of unselected autopsy cases [3]. Larger lesions are usually defined as adenomas, but in many cases, there are small, multiple, bilateral nodules [4]. They are more common with age and in patients with hypertension or diabetes mellitus [4, 5]. Their sizes range from microscopic to several centimeters. They are usually circumscribed but not encapsulated and the cut surface is yellow with focal brown areas. Most comprise ZF like cells. Some regard them as compensatory hyperplastic nodules following local ischemia and atrophy [4], while others have presented evidence that at least the larger nodules are neoplastic.
These nodules are now identified commonly in life when the abdomen is scanned for other disease, forming the major proportion of so-called adrenal incidentalomas [6]. High-resolution CT scans can detect lesions in about 4% of people [7]. They are more common in older people with a prevalence of about 7% over 70 years of age [8]. Some are found to be functional and others are associated with subclinical Cushing’s syndrome [9]. These are often removed. There is still debate as to how to deal with the non-functioning nodule [10]. Decisions may be made on the basis of size or evidence of growth, since larger adrenal cortical tumors are more likely to be malignant.
Adrenal Cortical Adenomas
The true incidence of adrenal adenomas is unknown as, until recently, most were diagnosed in life only if associated with autonomous hormone secretion. A recent autopsy study has suggested an incidence of about 5% [11]. Women are more frequently affected. The tumor is usually unilateral and solitary (Fig. 1), although bilateral adenomas have been reported [12]. They are intra-adrenal and may be unencap- sulated, show a true capsule or a pseudocapsule. The cut surface is usually yellow with focal brown areas. Histolog- ically, most comprise mainly lipid-laden ZF-like cells arranged in an alveolar pattern (Fig. 2). However, compact cells may predominate in adenomas associated with virilization, and this may cause problems in the assessment of malignant potential, as discussed below. Some contain lipofuscin and/or neuromelanin most marked in the ‘black adenoma’ [13]. This has no behavioral significance.
Adrenal Cortical Carcinomas
Adrenal cortical carcinoma (ACC) is a rare but highly aggressive tumor with an estimated prevalence of between 0.5 and 12 per million [6, 14-16]. It accounts for 0.05% to 2% of all malignancies [17-19]. Women are more com- monly affected. There is a bimodal age distribution, with a peak in early childhood and a second in the fifth to seventh decades. The prognosis is very poor, with 67% to 94% mortality. The median or mean survival from diagnosis lies between 4 and 30 months. Many are locally invasive, and between 15% and 67% have metastasized at the time of first presentation. The most common sites of metastasis are liver, lung, retroperitoneum, and lymph nodes.
Functioning tumors comprise between 24% and 74% of cases. Cushing’s syndrome is most common, often accom-
panied by androgen excess (mixed Cushing’s syndrome). Virilization may occur alone; feminizing tumors are rare. Other symptoms include abdominal or loin pain, abdominal fullness, and fever. Most weigh more than 100 g, but small tumors have behaved in a malignant fashion. Grossly, they may appear encapsulated or may be obviously adherent to or infiltrating surrounding structures. Lobulation is common with fibrous tissue separating tumor nodules. The cut surface is fleshy, with variable coloration ranging from pink/brown to yellow. Hemorrhage and necrosis are common (Fig. 3) and there may be cystic change. In occasional cases, there is gross evidence of vascular invasion.
Histologically, the architecture is less ordered than in adenomas. Trabecular and diffuse patterns of growth are seen and compact cells often predominate (Fig. 4). Nuclear pleomorphism is common (Fig. 5), sometimes with multi- nucleated giant cells. Mitotic activity is usually present
cm
often with atypical forms. Oncocytic variants have been described [20]. Broad fibrous bands (Fig. 6) are present in many cases and confluent necrosis is common. Both sinusoids and veins may be invaded and capsular invasion can be seen. Both local invasion and distant metastasis define malignancy.
Diagnosis of Malignant Potential and Prognostic Markers
As discussed above, the diagnosis of carcinoma is easy in many cases. However, the risk of malignant potential must be assessed in intra-adrenal lesions. This is best done by a combination of clinical, biochemical, and histologic find- ings. Features to be assessed have been identified by examining differences between tumors with known benign and malignant outcome. A number of protocols for
2
diagnosis based on multifactorial analysis have been published. In some, there is a combination of clinical, biochemical, and morphologic features that have been given a numerical weighting [21, 22]. The sum of the scores defines the tumor as adenoma, of uncertain malignant potential, or carcinoma. However, the pathologist may not have the clinical and biochemical information and may be limited to a histologic assessment. Weiss [23, 24] assessed nine features (Table 1), and the presence of any three of these indicated malignant potential. This system is widely used by pathologists. It was validated in a more recent study [25] with a specificity of 96% and sensitivity of 100%, and there was good correlation between pathologists in the overall score (r=0.94). However, there was poorer correlation on some of the individual features including nuclear pleomorphism and vascular invasion, and the group proposed omitting these features and incorporating the others into a weighted numerical score. The modified Weiss system [25] has recently been compared to that of van Slooten in classifying tumors [26]. They found that the two indices performed equally well in distinguishing adenomas from carcinomas, although they assess different features.
Table 1 Diagnosis of malignancy in adrenal cortical tumors Histological features to be assessed
Diffuse architecture greater one third Clear cells ≤25% of total Significant nuclear pleomorphism Confluent necrosis Mitotic count ≥6 per 50 high power fields Atypical mitoses Capsular invasion Sinusoidal invasion
Venous invasion
However, not all systems may give the same diagnosis in an individual case [26]. In difficult cases, all clinical and histologic information should be taken into account. In a few cases, a diagnosis of indeterminate or borderline tumor may have to be made.
An area where there is difficulty in applying the Weiss criteria is that of oncocytic tumors. This is because most have less than 25% clear cells, pleomorphic nuclei, and diffuse architecture (Fig. 7), thus immediately classifying them as malignant if the standard Weiss criteria are applied. A more recent publication [27] has proposed the following approach modified from Weiss. They have defined three major criteria: a mitotic rate of greater than five mitoses per 50 high power fields, any atypical mitoses, and venous invasion. The presence of any one of these defines the tumor as malignant. Four minor criteria are also recog- nized: large size (>10 cm or >200 g), necrosis, capsular invasion, and sinusoidal invasion. Identification of one or more of these categorizes it as of uncertain malignant potential. If none of these features is present, the tumor is diagnosed as benign. Other studies have used a similar approach to diagnosis [28, 29], but have not been so precise in the definition of how to apply the criteria. This appears a sensible approach, but it will have to be validated prospectively.
A few additional investigations are emerging. The Ki-67 (MIB-1) index is higher in some carcinomas with levels of more than 4-5% seen only in malignant lesions [30, 31]. However, a low Ki-67 index does not define behavior, as many carcinomas have levels below this threshold. Adrenal carcinoma is associated with overexpression of IGF-II [32, 33] which can be detected by immunohistochemistry. Abnormal expression of p53 protein and p53 mutations
are present in the majority of carcinomas and rarely in adenomas, so again, immunopositivity is supportive of a malignant diagnosis [34-36].
High proliferative activity is associated with more aggres- sive behavior, tumors with a mitotic rate greater than 20 per 50 HPF having a poorer survival [23]. A Ki-67 index of greater than 3% [35] was associated with a shorter disease-free interval. In the study comparing modified Weiss and van Slooten systems [26] both correlated with survival, patients with higher scores have a poorer outcome. The Aubert system [25] also correlated with disease-free survival.
Staging of Adrenal Cortical Carcinoma
Neither the American Joint Committee on Cancer nor the International Union against Cancer has a formal staging system for adrenal cortical cancer. The most commonly used system is the modification [37] of the original proposal of MacFarlane [19] (Tables 2 and 3). Outcome is linked to stage.
Adrenal Cortical Hyperfunction
Response to Stress
Chronic stress causes increased output of ACTH and increased stimulation of the adrenal cortex. Adrenal weight increases with enlargement of ZF and ZR. This is probably a combination of hypertrophy, hyperplasia, and reduced apoptosis [38, 39]. Lipid depletion occurs in the ZF in a centrifugal manner. Degenerative changes may be seen in the outer ZF with cords of cells converted into tubular structures [40]. Lipid reversion is characterized by reac- cumulation of lipid, also in a centrifugal manner. Care should be taken not to misinterpret outer lipid depleted cells as hyperplastic ZG. These changes are often seen in hospital autopsies and sometimes in glands removed for pheochromocytoma or along with renal tumors.
| Criteria | |
| T1 | Tumor ≤5 cm, no invasion |
| T2 | Tumor >5 cm, no invasion |
| T3 | Tumor any size, locally invasive, not invading adjacent organs |
| T4 | Tumor any size, invading adjacent organs |
| N0 | Negative regional nodes |
| N1 | Positive regional nodes |
| M0 | No distant metastases |
| M1 | Distant metastases |
| Stage | |
| I | T1N0M0 |
| II | T2N0M0 |
| III | T1N1M0 |
| T2N1M0 | |
| T3M0N0 | |
| IV | Any T, any N, M1 T3N1 |
| T4 | |
Chronic Hypersecretion of Hormones
Three classical clinical syndromes are associated with hypersecretion of adrenal cortical steroids: primary hyper- aldosteronism (including Conn’s syndrome), Cushing’s syndrome (hypercortisolism), and adrenogenital syndrome (hypersecretion of sex steroids).
Primary Hyperaldosteronism
Historically, this has been thought to be a rare cause of hypertension, accounting for less than 1% of patients attending clinics, although some would say it is responsible for up to 10% of cases [41, 42]. There are high aldosterone levels with low renin and hypokalemia. About two thirds of patients have classical Conn’s syndrome with an adrenal adenoma. Carcinomas are extremely rare. The tumors are usually small, often less than 2 cm in diameter and half weigh less than 4 g. Women are more commonly affected than men, with a peak incidence in the third to fifth decades [43]. The cut surface has a golden yellow color. Histologic examination shows various cell types. Most resemble ZF cells with only a minority of ZG morphology. Hybrid cells show mixed features, containing lipid but with a higher nuclear to cytoplasmic ratio than ZF cells. Compact cells are also found. The para-adenomatous gland often contains micronodules. The adjacent ZG may be normal but may be hyperplastic. Whether this relates to the pathogenesis of the disease or is an effect of treatment is unclear. Where spironolactone has been given, small whorled globular intracellular inclusions, known as spironolactone bodies, may be seen in the ZG and outer ZF (Fig. 8) and in the tumor itself. These are probably derived from smooth endoplasmic reticulum.
Bilateral hyperplasia of the ZG, so-called idiopathic hyperaldosteronism, is now more commonly recognized. Instead of the normal focal distribution, the ZG usually forms a continuous subcapsular band and may extend into the ZF, but unless nodules are present, the glands are of normal weight. Other cases may be associated with unilateral nodular hyperplasia [44].
Cushing’s Syndrome
The clinical features associated with hypercortisolism are well known. Two thirds of cases are due to hypersecretion of ACTH by the anterior pituitary gland-Cushing’s disease. About 90% of these patients have a pituitary corticotroph adenoma. In most cases, the adrenals show bilateral diffuse cortical hyperplasia, each gland weighing 6-12 g. The cortex is broadened with a relative increase in the width of the ZR. Microscopic nodules are not uncommon, usually in the outer ZF. Ten percent to 20% of patients have bilateral nodular (or macronodular) hyperplasia. In the past, this diagnosis was restricted to glands with nodules visible to the naked eye and was usually made by the pathologist. It is also now applied when multiple nodules are seen on CT scan, which can currently detect those of 6 mm or more in diameter. The intervening cortex is diffusely hyperplastic and the nodules merge with it. Diffuse and nodular hyperplasia may be a continuum, nodules developing in long-standing disease. The emergence of adrenal autonomy in occasional cases suggests that neoplastic transformation can occur on a background of hyperplasia [45].
Ectopic ACTH syndrome accounts for 15% of cases, about half caused by bronchial carcinoid or small-cell lung carcinoma. Other tumors associated with the syndrome are thymic carcinoids, islet cell tumors of pancreas, medullary
carcinoma of thyroid, and pheochromocytoma. The adre- nals show marked bilateral symmetrical enlargement weighing on average 15 g each and rarely contain nodules. Compact cells extend close to the capsule, mitotic figures may occasionally be found, and pleomorphism is common.
Fifteen percent to 20% of adults have an adrenal tumor equally divided between benign and malignant and most common in the fourth and fifth decades. In contrast, more than 50% of children with the disease have a tumor, the majority malignant. Females are affected four times as often as males. Coexistent virilization is more common in carcinomas. Because the high levels of cortisol suppress ACTH secretion from the pituitary, the ZF and ZR of the adjacent cortex and the contralateral gland are atrophic. The ZG may appear more prominent than in the normal gland due to the relative loss of the other two zones.
A rare variant is macronodular hyperplasia without ACTH hypersecretion [46, 47]. The glands are markedly enlarged and distorted. The nodules are composed mainly of lipid-laden cells and the intervening cortex can be difficult to recognize, but has been reported atrophic. ACTH levels are suppressed. Some of these cases are due to the aberrant or ectopic expression of receptors for a range of signaling molecules [48], including those for gastric inhibitory polypeptide (GIP) and luteinizing hormone [49]. In patients with GIP receptor expression, the hypersecretion of cortisol is linked to intake of food [50]. Occasional adenomas also express aberrant receptors [51].
Primary pigmented nodular adrenocortical disease is a rare familial condition of children and young adults. Patients have features of Cushing’s syndrome, but osteopenia is severe. Both glands usually consist of multiple small brown to black nodules and the combined weights range from 4 to 21 g. The remaining cortex may be difficult to identify and appears suppressed. Plasma ACTH levels are low, consistent with adrenal autonomy. In some patients, this forms part of the Carney complex [52].
Adrenogenital Syndrome (Sex Steroid Excess)
Excess production of sex steroids causes virilization, feminization, or precocious puberty, depending on the steroids secreted and the age and sex of the patient. Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases affecting cortisol synthesis [53, 54]. In most forms, mutations or translocations of genes encoding the steroidogenic enzymes result in inefficient steroidogenesis with decreased negative feed- back to the pituitary. This results in increased secretion of ACTH, with adrenocortical hyperplasia. The glands have a characteristic cerebriform appearance and the cortex is lipid-depleted. There is a higher frequency of adrenal cortical tumors than in the general population, suggesting
that chronic stimulation by ACTH may have a role in tumorigenesis [55]. Myelolipomas have also been reported [56, 57]. Congenital lipoid hyperplasia is a very rare cause of CAH, and the histological appearance of the gland differs from the other variants with accumulation of lipid within the cells. This is now known to be associated with mutations in steroid acute regulatory protein that transports cholesterol to the mitochondria [58]. The accumulation of cholesterol in the cytoplasm causes the unusual histological appearance.
Adrenal cortical tumors may also produce sex steroids, usually androgens, either alone or in combination with cortisol (mixed Cushing’s syndrome). Eighty percent of cases are in females and the majority in children. Estrogen- secreting tumors most frequently present as feminization in men, but are an occasional cause of precocious puberty in girls. A higher proportion is malignant, particularly in feminizing cases. The usual criteria must be applied to distinguish benign and malignant potential, but there are some caveats. Tumor weights are extremely variable and even benign tumors may be very large. Also, compact cells are more common in androgen-secreting adenomas than in other subtypes.
Differential Diagnosis
Occasionally adrenal cortical carcinoma may have to be distinguished from hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), or pheochromocytoma. Antibody D11 has been reported useful in identifying adrenal cortical tumors [59], as have immunoreactivity for inhibin-& (Fig. 9) [60, 61] and with melan-A clone A103 [62]. Immunopositivity for SF-1 and DAX-1, nuclear factors
important in steroidogenesis [63, 64], is not yet widely used in diagnostic practice. Immunopositivity for cytokeratins is weak or absent and they are negative for epithelial membrane antigen. RCC is usually positive for both of these. HCC may be positive for x-fetoprotein, «1-antitrypsin, and CEA. ACC can show positive staining for general neuroendocrine markers including synaptophysin, so chromogranin A is the only marker that will positively discriminate between ACC and pheochromocytoma [65].
Molecular Pathogenesis of Adrenal Cortical Tumors
Although information on molecular pathogenesis is accu- mulating, it has not yet really impinged on diagnostic or prognostic testing. Comparative genomic hybridization, loss of heterozygosity (LOH), and interphase cytogenetics have been used to examine changes in individual chromo- somes, but conflicting data have emerged. Changes have been reported in between 28% [66] and 51% [67] of adenomas. Losses have been found on chromosomes 1p, 17p, 22p, 22q, and 11q and gains on 5, 12, 19, and 4 [67]. LOH or allelic imbalance have been demonstrated at 11q13 (≥90%), 17p13 (≥85%), and 2p16 (92%) in carcinomas [66, 68]. Changes in chromosomes 3, 9, and X may be early events, and there is evidence of accumulation of changes in tumor progression [67, 69].
A number of oncogenes and tumor suppressor genes have been investigated. ACC occurs in Li-Fraumeni syndrome, associated with germline mutations in the p53 gene [70]. The majority of sporadic ACC also show abnormal p53 expression and/or p53 mutations, while few adenomas do [35, 36, 71]. An unusual inherited mutation in the p53 gene is thought to account for the high numbers of childhood adrenal carcinomas in Brazil and is also found in a proportion of the adult cases [72]. Conflicting data exist on the RAS family of oncogenes with some studies reporting involvement of some members of the family [36, 73-75]. Somatic mutation of the MEN1 gene is rare [76].
Familial tumors also occur in Beckwith-Wiedemann syndrome, associated with dysregulation of a group of growth controlling genes on 11p15.5 [77] including paternal disomy of the IGF-II gene. Rearrangement at this locus and overexpression of IGF-II has been reported in the majority of sporadic cases of carcinoma [33, 78]. Other growth factor interactions which may be involved are TGF& and epidermal growth factor receptor IGF-I, its binding proteins and receptors [33, 79, 80], and the activins and inhibins [60, 61, 81]. Mutations in the ACTH receptor are found in a subset of adrenal cortical tumors but are probably not of major importance in pathogenesis [82].
A microarray study using 10,000 genes [83] has confirmed IGF-II as important in carcinoma and has
identified new candidate genes including fibroblast growth factor receptor 1, osteopontin, and 11ß-hydroxylase (CYP11B1). A separate investigation [84] examined cancer- related genes and adrenal-cortex-related genes, including steroidogenic enzymes, cAMP signaling components, and the IGF-II system. Using a combination of eight genes from the IGF-II cluster and 14 from the adrenal cluster, the predictive value for malignancy was similar to that of the Weiss histological score. The adrenal cluster was more highly expressed in adenomas and the IGF-II cluster in carcinomas. In addition, using expression profiles of 14 genes, it was possible to separate recurring from non- recurring tumors in a group of 13 carcinomas.
Other Lesions
Myelolipomas comprise a mixture of mature adipose tissue and hemopoietic tissue. Their histogenesis has not been clear, but the recent demonstration of clonality in both elements suggests that they are neoplastic [85]. Focal myelolipomatous change may be seen in other adrenal cortical tumors and in cortical hyperplasia.
Adrenal cysts are rare lesions [86-88]. Most are small and are incidental findings at autopsy. Endothelial cysts comprise about 45% of cases and most are thought to arise from lymphatics. A small proportion appears to be hemangiomatous. The lining cells may be immunopositive for CD31 and CD34. Pseudocysts (39%) are the next most common. They have fibrous walls, usually with no obvious lining. Groups of adrenal cortical cells are scattered within the fibrous tissue and there is often calcification. The contents consist of organizing thrombus and bloodstained fluid. They are probably a heterogeneous group, some the result of adrenal hemorrhage and others representing degeneration in an endothelial cyst or adrenal tumor. This group is the most common to present clinically. Epithelial cysts account for 9% and are either degenerate neoplasms or, rarely, retention or embryonal cysts. In some countries, parasitic cysts are more common, accounting for 7% overall. These are usually due to echinococcal infection.
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